The activation of proto-oncogenes is a general mechanism of carcinogenesis. Induction of breast cancer in mice by the retrovirus, mouse mammary tumor virus (MMTV), results from proviral insertion in the vicinity of one of a series of proto-oncogenes (the int-x, or wnt-x series) and activation of these genes uniquely in mammary cells. We have established that tissue specific expression for MMTV results from at least three separate elements. A tissue specific enhancer was discovered at the 5' end of the LTR, and two activities that interact with this enhancer have been identified. An immediate proximal promoter element, the TATA region, which binds the critical TFIID component of the basal preinitiation complex, has also been found to confer mammary specific expression in vitro. Finally, an as yet poorly defined internal region of the viral LTR appears to harbor a negative element that may also be involved in tissue targeting. We propose that the upstream tissue specificity element (TSE) forms that basis of mammary specific oncogene activation. This element can function to activate heterologous promoters in a cell-specific and hormone-independent fashion. The activities that interact with this locus are also present and active in human breast cancer cells, arguing that this mechanism of tissue specific expression is conserved across the murine and human species. These observations further suggest that this mechanism of mammary specific expression may be func- tioning in the inappropriate expression of genes in human breast cancer.